The metabolites of arachidonic acid, such as prostaglandins, lipoxygenases and thromboxane products are produced in a wide variety of tissues and play a key role in several biological responses. Prostaglandins mediate both beneficial and undesirable biological reactions. The production of prostaglandins induces pain, swelling, heat and redness which are characteristic features of inflammation. The chronic inflammation associated with prostaglandin production leads to the breakdown of the injured tissue and angiogenesis. In pathologic chronic inflammation, normal tissues can be destroyed and the new blood vessel formation can support growth of abnormal tissue. Prostaglandins are also important for normal physiological processes in different organs. In the stomach, prostaglandins protect mucosa from acid. They also regulate blood flow and salt-water balance in the kidney. Prostaglandins are also important in platelet aggregation and participate in memory and other cognitive functions.
Prostaglandins are produced from cell membrane phospholipids by a cascade of enzymes. The enzymatic activities involve release of arachidonic acid from the cell membrane by phospholipase A2, followed by the conversion of arachidonic acid to a common prostaglandin precursor, PGH2, by cyclooxygenase (also called prostaglandin H synthase). PGH2 is finally converted to various types of prostaglandins (PGE1, PGE2, PGI2 or prostacyclin, PGF2α and thromboxane) by cell-specific synthases.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAID's) block the formation of prostaglandins by inhibiting cyclooxygenase activity. They have analgesic, antipyretic and anti-inflammatory activities. However, chronic treatment with the available NSAID's often leads to disruption of beneficial prostaglandin-mediated processes. The side effects associated with constant usage of NSAID's include gastrointestinal (GI) irritation and formation of life-threatening GI ulcers.
A dramatic advance in the field of inflammation research came with discovery of multiple enzymes for each step of the prostaglandin synthase cascade. The research suggested that in some situations, such as inflammation, cyclooxygenase was inducible. The cyclooxygenase known at the time, cyclooxygenase-1 (COX-1), was clearly non-inducible or modulated by glucocorticoids. A second, inducible form of cyclooxygenase known as cyclooxygenase-2 (COX-2) was subsequently identified and cloned by several groups of investigators. COX-1 is the constitutive cyclooxygenase isoform and is mainly responsible for the synthesis of cytoprotective prostaglandins in the GI tract and the synthesis of thromboxane which triggers platelet aggregation in blood platelets. COX-2 is inducible and short lived except in the case of certain tumors where it is constitutively activated. COX-2 expression is stimulated in response to endotoxins, cytokines, hormones, growth factors and mitogens. These observations suggest that COX-1 and COX-2 serve different physiological and pathophysiological functions. Indeed, it has been suggested that COX-1 is responsible for endogenous basal release of prostaglandins and hence is important to the physiological functions of prostaglandins such as GI integrity and renal blood flow. On the other hand, it has been suggested that COX-2 is mainly responsible for the pathological effects of prostaglandins, where induction of the enzyme occurs in response to inflammatory agents, hormones, growth factors and cytokines. See, U.S. Pat. No. 5,604,253, incorporated herein by reference, for a discussion of the advantages of selective COX-2 inhibition. Principally, a selective COX-2 inhibitor is expected to possess similar anti-inflammatory, antipyretic and analgesic properties to a conventional NSAID but with reduced potential for gastrointestinal toxicity, and a reduced potential for renal side effects.
The differential tissue distribution of COX-1 and COX-2 provides an approach to develop selective inhibitors for COX-2 with reduced effect on COX-1, thereby preventing gastric side effects.
A number of selective COX-2 inhibitors have been reported. These include diaryl heterocyclics (Penning et al., J. Med. Chem, 40, 1347–1365 (1997); acetoxyphenyl alkyl sulfides (Kalgutkar et al., J. Med. Chem, 41, 4800–4818 (1998); methane sulfonanilides (Li et al., J. Med. Chem, 38, 4897–4905 (1995); and tricyclic inhibitor classes (Wilkerson et al., J. Med. Chem., 38, 3895–3901 (1995). U.S. Pat. No. 5,604,253 discloses N-benzylindol-3-yl propanoic acid derivatives as cyclooxygenase inhibitors.
What are needed are additional COX-2 inhibitors, particularly compounds which selectively inhibit the cyclooxygenase activity of COX-2 over COX-1.